Field of the Invention
The present disclosure concerns rat models having a hepatic deficiency and/or an immunodeficiency and their use. This disclosure also relates to methods of using such animal models, including expanding heterologous hepatocytes, such as human hepatocytes, in such animal models.
Description of Related Art
The liver is the principal site for the metabolism of xenobiotic compounds including medical drugs. Because many hepatic enzymes are species-specific, it is necessary to evaluate the metabolism of candidate pharmaceuticals using cultured primary human hepatocytes or their microsomal fraction. While microsomal hepatocyte fractions can be used to elucidate some metabolic functions, other tests depend on living hepatocytes. Some compounds, for example, induce hepatic enzymes and thus their metabolism changes with time. To analyze enzyme induction, hepatocytes must be not only viable, but fully differentiated and functional.
Human hepatocytes are widely used by the pharmaceutical industry during preclinical drug development. Their use is mandated by the FDA as part of drug development. For drug metabolism and other studies, hepatocytes are typically isolated from cadaveric organ donors and shipped to the location where testing will be performed. The condition (viability and state of differentiation) of hepatocytes from cadaveric sources is highly variable and many cell preparations are of marginal quality. The availability of high quality human hepatocytes is further hampered by the fact that they cannot be significantly expanded in tissue culture. After plating, the cells survive but do not divide. Hepatocytes from readily available mammalian species, such as the mouse, are not suitable for drug testing because they have a different complement of metabolic enzymes and respond differently in induction studies. Immortal human liver cells (hepatomas) or fetal hepatoblasts are also not an adequate replacement for fully differentiated adult cells. Human hepatocytes are also necessary for studies in the field of microbiology. Many human viruses, such as viruses that cause hepatitis, cannot replicate in any other cell type.
Moreover, bioartificial liver assist devices, which use hepatocytes ex vivo, have been used to support patients in acute liver failure. In addition, several clinical trials of hepatocyte transplantation have been carried out, which provided proof-of-principle that hepatocyte transplantation can be beneficial. Currently, human hepatocytes cannot be expanded significantly in culture. Hepatocytes derived from stem cells in culture are immature and generally lack full functionality. Therefore, all hepatocytes in use today are derived from human donors, either cadaveric or surgical specimens, which significantly limits hepatocyte availability. If enough human hepatocytes were available, bioartificial liver assist devices would become a viable technology and human hepatocyte transplantation could find wide-spread use. Given these limitations, methods of expanding primary human hepatocytes are highly desirable. There is also a need in the animal health industry for processes to expand hepatocytes from other species, such as dogs, horses, etc. for research and study.